Pentamidine [1,5-bis(4-amidinophenoxy)pentane] is a trypanocidal compound which is particularly active against Leishmaniasis. It unfortunately suffers from a large number of side-effects and has now been substantially displaced by other drugs. However, it is also active against pneumocystis carinii pneumonia (PCP)--one of the commonest, lethal, opportunistic infections suffered by AIDS patents--having utility as both a curative and prophylactic agent.
Due to the instability of aqueous pentamidine solutions, the material is normally supplied in the form of its isethionate (2-hydroxyethanesulphonate), as a powdered material to be reconstituted with water immediately prior to administration by injection or infusion. This means that the patient still suffers from the side effects. Although these are more acceptable in the treatment of a potentially lethal infection, it is nevertheless desirable to overcome them if at all possible. With this in mind it is clearly advantageous to administer the drug directly to the site of infection, i.e. to the lungs.
Therefore pentamidine isethionate is now used in solution in nebulizers for administration by inhalation. Not only does this result in direct treatment of the infected site, but also absorption from the lungs is relatively limited, so that the side effects are substantially reduced.
Because of the abovementioned instability in solution it is still necessary to supply the material in the form of an ampouled solid, which is dissolved in water before use. This is a relatively troublesome process and involves the use of needles and syringes (clearly undesirable for many AIDS patients). It would therefore be highly desirable to produce pentamidine in a stabilized solution form, which can be placed directly into a nebulizer when required for use.
It has been found that pentamidine is more stable in acidic than in alkaline aqueous media. However the production of usable solutions appeared to be impossible as heretofore pentamidine has been found to be insoluble in, or precipitated or salted out by, buffer solutions which are also pharmaceutically and pharmacologically acceptable at concentrations normally used. This was not unexpected in view of the known difficulty of solublizing pentamidine and the need to use unusual anions such as isethionate when a water soluble form of pentamidine was required.